FEBRILE NON HEMOLYTIC TRANSFUSION REACTION

A COMPREHENSIVE APPROACH
FOR DIAGNOSIS AND DESCRIBING FNHTR WITH LATEST DATA

1. FEBRILE NON HEMOLYTIC TRANSFUSION REACTION DR AKSHAYA TOMAR DEPT OF IMMUNOHEMATOLOGY AND BLOOD TRANSFUSION AFMC,PUNE

2. INTRODUCTION Transfusion reactions are a diverse group of adverse events occuring as a result of transfusion that usually present during or after transfusion. No single alogrithm can encompass all types of events.

3. DEFINITION Temperature increase of at least 1°C with or without chills ,a cold sensation or discomfort Occurrence during or within few hours of transfusion Unrelated to hemolysis,sepsis or other known causes of fever Most severe reaction – rigors ; temp rise of > 2°C Fever usually persist for no more than 8-12 hrs

4. FNHTR Chills with or without an increase in body temperature can be classified as an FNHTR if other causes of chills are unlikely Fever increases O 2 Consumption (13% for every 1°C over 37°C) An asymptomatic rise in temperature in a hypothermic patient should not be considered as FNHTR

5. Problem statement Most frequent reported reaction Incidence – 0.1% to 1% (decreased after ULR) Mostly due to transfusion of cellular components (RBCs, Platelets , Granulocytes and even IVIG) Higher incidence for platelets(4.6%) than for RBCs (0.33%) Not life threatening but prompt evaluation is required In addition to the toll taken by the patients, there is an inevitable system cost with the management of these events

6. ETIOLOGY FNHTR appears to be a part of Systemic inflammatory response syndrome 2 possible underlying causes: a) Classical – leukocytes stimulate the in vivo generation of cytokines in the recipient b) Non-Classical – Pyrogenic cytokines or other inflammatory response mediators(activated complement proteins , LPS or neutrophil -priming lipids) that accumulate in the plasma portion of cellular blood components during storage

7. ETIOLOGY Alloimmunization to leukocytes/platelets - FNHTR risk increases with increase in passenger leukocytes - Donor Ab to leukocytes (most often have HLA specificity) associated with FNHTR less frequently - 1 X 10 7 leukocytes / unit of RBCs is the minimum number necessary for FNHTR - Possible mechanism by which Ab -leukocyte or Ab -platelet interaction causes fever : 1) Donor monocytes may be activated and secrete pyrogenic cytokines when recipient Ab bind to them 2) Immune complex formation between recipient Ab and donor leukocytes leads to generation of activated complement components which stimulates production of PGE2

8. ETIOLOGY Storage generated cytokines Ab to leukocytes/platelets do not appear to account for all FNHTRs, particularly those caused by platelet transfusions In addition,rate of FNHTR to platelet transfusion increases with increasing storage duration The discovery that proinflammatory cytokines accumulation may account for many of these findings ( IL1 β ;IL6;TNF α ;MIP1 α ;GRO α ) Platelet derived CD40L has been associated with FNHTR Prestorage or early storage leukocyte reduction prevents or greatly reduces generation of these cytokines Stimulus for Cytokine generation -> remains unknown

9. ETIOLOGY RBC units are stored at 2-6°C which has an inhibitory effect on cellular metabolism, the capacity of passenger leukocytes in RBC units to synthesize and secrete cytokines is less than those in platelet concentrate. Unless a Gram’s stain and bacterial culture is performed,mild septic transfusion reactions characterized by only fever and chills are likely to be classified as FNHTR.

10. PATHOGENESIS

11. PATHOGENESIS CLASSICAL NON-CLASSICAL COMMON PATHWAY IL1 β ;IL6;TNF α HYPOTHALAMUS THERMOREGULATORY CENTER EP3 RECEPTORS PGE2 FEVER

12. DIAGNOSIS Vitals monitoring both pre and post transfusion should be performed,particularly in the first 30-60 min Rule out other causes of febrile reaction like acute hemolysis /sepsis/TRALI as FNHTR is a diagnosis of exclusion

13. Differential Diagnosis Acute hemolytic reaction Bacterial contamination TRALI Disease / treatment related fever

14. Differential Diagnosis

15. Febrile reactions in infants Infants are incapable of shivering It is not unusual to observe rise in temperature up to 38.5°C after transfusion Temporary refusal to feed , diarrhoea , sudden pallor and cold skin are other markers of FNHTR

16. Effect of rate of infusion Slower infusion avoids a sudden bolus of bacterial toxins or cytokines that may provoke an immediate and possibly massive inflammatory response

17. Treatment Transfusion in progress should be discontinued Antipyretics , Acetaminophen(325-500mg) can be administered – (unsupported , self limiting fever) Diphenhyramine (50-100mg) – No role Rigors will not respond promptly to antipyretic medications Meperidine (25-50mg) administered intravenously for rigors (contraindicated in renal failure and patients on MAO inhibitors)

18. Prevention Consider prevention if patient has had more than 2 FNHTR Administer paracetamol 1g po 1-3 hours before transfusion efficacy of premedication has not been established (advantages: no serious ADR; it doesn’t mask HTR/sepsis) Meperidine / Diphenhydramine /Steroids – not indicated

19. Prevention Transfused component should have < 5 X 10 6 leukocytes/unit Using fresh blood and components <7days (<4d for PC) Reduce the transfusion rate to 75ml/hr Accumulated inflammatory mediators can be removed by plasma expression Keep patient warm

20. Should we restart transfusion? The principal argument in favor of restarting transfusion is the reduction in the number of Donor exposures ( esp in pooled platelet conc ) Arguments against restarting the transfusion include the possibility that the patient may have a continued febrile reaction to the unit, and if a hemolytic reaction or bacterial contamination has not been definitively excluded Decision to restart depends on – clinical condition, transfusion reaction testing results and hospital transfusion policy

21. LEUKOREDUCTION

22. INTRODUCTION A unit of Leukocyte reduced blood/component must contain no more than: - 1 X 10 6 leukocytes as per European guidelines - 5 X 10 6 leukocytes as per US guidelines 1 X 10 6 leukocytes translates into 3.3 WBCs/µl Many centers have implemented universal leukocyte reduction(ULR) to avoid difficulties in managing 2 different inventories.

23. Leukoreduction Poststorage leukoreduction suffices in case of RBC transfusions In several studies It was proven that removal of 75-90%(1 Log reduction) from PRBCs to below 5 X 10 8 / Unit prevented FNHTR even in multi transfused patients For transfusion of RDP , prestorage filtration is more effective as cytokine production continues at 22-24°C

24. Selected countries where ULR is practiced European Non European Austria Canada Belgium Qatar Finland Japan Netherlands New Zealand Norway Australia Romania Spain France Germany Ireland Portugal Switzerland

25. Techniques for Leukoreduction Centrifugation and buffy coat removal (1 Log reduction) Cell washing(1-2 Log reduction) Filtration(3-4 Log reduction) Apheresis (3-4 Log reduction) Freezing and deglycerolization (2-3 Log reduction)

26. Clinical Benefits of Leukoreduction Clinically proven: - Reduced frequency and severity of FNHTR - Reduced risk of Cytomegalovirus transmission - Reduced risk of HLA- alloimmunization (especially in organ transplant patients) and platelet refractoriness - Reduced mortality , infection rates , hospital stay and organ dysfunction in cardiovascular surgery patients

27. Clinical Benefits of Leukoreduction Likely clinically relevant: - Reduced infectious risk associated with immunomodulation - Reduced direct risk of transfusion transmission of bacteria Unproven clinically: - Avoidance of variant Creutzfeldt - Jacob disease ( vCJD ) - Avoidance of HTLV I/II , EBV etc. -Reduced risk of Graft Versus Host Disease (GVHD) -Reduced risk of Transfusion Associated Acute Lung Injury (TRALI)

28. Prestorage Leukoreduction Advantages It eliminates the scope of inflammatory cytokine accumulation  prevention of FNHTR Minimizes the risk of HLA alloimunization as it removes intact leukocytes Minimizes the risk of leukotropic virus transmission as leukocytes disintegrates and release interacellular organisms after 72 hrs of storage It is always easier to perform QC in Lab rather than patient’s bedside

29. Cost Effectiveness of Leukoreduction In economically poor countries , cost of ULR remains cause of worry. One filter roughly costs around 900 – 1700 INR in India and around 20-40 USD An European study estimated cost of prevention of 1 FNHTR is about 6,916 EUR Recent retrospective study in Canada revealed that 1 life was saved for every 120 patients who received LR blood However trend is still in favor of ULR in wealthy countries

30. Hemovigilance Programme of India: T x Reactions Analysis from Jan 2013 to Apr 2016 Total reactions reported 3903 FNHTR 1594(40.84%) Most cases are due to PRBCs 1260 Least cases are due to apheresis platelets 8 FNHTR after first transfusion episode 1140

31. BIBLIOGRAPHY Rossi’s principle of Transfusion medicine, 5 th edition Transfusion Therapy: Clinical Principles and Practice, Mintz , 3 rd edition Mollison’s Blood transfusion in clinical practices , 12 th edition

32. THANK YOU